Biology subjects

Leroy, D.

Publications and source records attributed to Leroy, D..

5 recordsLinked to original sources

bioRxiv2026

Multidimensional in vitro assay for antimalarial combination testing and pharmacodynamic modeling - the MULT-i2 assay

Malaria remains a major global health challenge, with emerging partial resistance to first-line therapies in Africa threatening current control efforts. Drug combinations are essential to improve treatment efficacy and restrain resistance development. However, in vitro assays that quantify parasite viability after drug exposure and characterize pharmacodynamic drug interactions are labor- and resource-intensive, with standard approaches such as the parasite reduction ratio assay limiting systematic, high-resolution evaluation of drug combinations. We present the MUltidimensional Luminescence Test for integration of interactions (MULT-i2), an in vitro assay that enables scalable, high-resolution assessment of parasite viability across multidimensional drug concentration spaces. For dual drug combinations, the MULT-i2 assay characterizes interaction surfaces while requiring [~]50-fold fewer resources and more than two-fold less time than conventional methods, enabling exploration of broader combination scenarios. The assay combines a highly sensitive chemiluminescence readout with inducible reporter expression in Plasmodium falciparum, supporting potential extension to multidimensional combination testing. Using the general pharmacodynamic interaction (GPDI) model, the MULT-i2 assay quantified interaction potency and directionality, confirming and refining the known synergy between atovaquone and proguanil, and revealing detailed interaction patterns for additional drug combinations. Overall, this approach provides an efficient framework for testing and characterizing pharmacodynamic drug interactions and supports the rational development of antimalarial combination therapies.

microbiology↗

bioRxiv2024

An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs

Elimination and eradication of malaria will depend on new drugs with potent activity against Plasmodium falciparum mature stage V gametocytes, the only stages able to infect the mosquito vector for onward parasite transmission. The identification of molecules active against these quiescent stages is difficult due to the specific biology of gametocyte maturation and challenges linked to their cultivation in vitro. Furthermore, the antimalarial drug development pipeline lacks a suitable animal model for evaluating the transmission-blocking potential of promising lead compounds and preclinical and clinical drug candidates in vivo. Here, we established a transmission-blocking drug discovery and development platform based on transgenic P. falciparum parasites engineered to produce large numbers of pure stage V gametocytes expressing a red-shifted firefly luciferase as reporter for cellular viability. This NF54/iGP1_RE9Hulg8 line facilitated the development of a highly efficient and robust in vitro screening assay for the identification of stage V gametocytocidal compounds. Importantly, by infecting humanized NODscidIL2R{gamma}null mice with pure NF54/iGP1_RE9Hulg8 stage V gametocytes, we also established a preclinical P. falciparum in vivo transmission model. Using whole animal bioluminescence imaging and quantification of gametocyte densities over a period of 14 days, we assessed the gametocyte killing and clearance kinetics in vivo of antimalarial reference drugs as well as five clinical drug candidates and identified markedly different pharmacodynamic response profiles. Furthermore, we successfully integrated this mouse model with mosquito feeding assays and thus firmly established a valuable tool for the systematic in vivo evaluation of gametocytocidal and transmission-blocking drug efficacy. One sentence summaryWe applied robust new assays for gametocytocidal drug discovery and in vivo efficacy testing using a humanized mouse model for malaria transmission

microbiology↗

bioRxiv2023

Genetic complexity alters drug susceptibility of asexual and gametocyte stages of Plasmodium falciparum to antimalarial candidates

Withdrawal statementThe authors have withdrawn their manuscript owing to internal reviewing and agreement to submission by all parties involved in the work not yet completed on this version of the paper. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

biochemistry↗

bioRxiv2020

Effects of practice on a mechanical horse with an online feedback on performing a sitting postural coordination

The present research aims at quantifying the impact of practicing a new coordination pattern with an online visual feedback on the postural coordination performed on a mechanical horse. Forty-four voluntary participants were recruited in this study. They were randomly assigned to four practice groups based on i) with or without feedback (i.e., group 1, control, did not receive the feedback; group 2, 3 and 4 received an online feedback during practice) and ii) the specific trunk/horse coordination to target during practice (group 1, target coordination = 180{degrees} (without feedback); group 2, target coordination = 0{degrees}; group 3, target coordination = 90{degrees}; group 4, target coordination = 180{degrees}). All participants performed pre-, practice, post- and retention sessions. The pre-, post- and retention sessions consisted of four trials, with one trial corresponding to one specific target coordination to maintain between their own oscillations and the horse oscillations (spontaneous, 0{degrees}, 90{degrees}, and 180{degrees}). The practice phase was composed of three different sessions during which participants received an online feedback about the coordination between their own oscillations and the horse oscillations. Results showed a significant change with practice in the trunk/horse coordination patterns which persisted even after one month (retention-test). However, all the groups did not show the same nature of change, evidenced by a high postural variability during post-test for 0{degrees} and 90{degrees} target coordination groups, in opposition to the 180{degrees} and spontaneous groups who showed a decrease in coordination variability for the 180{degrees} group. The coordination in anti-phase was characterized as spontaneously adopted by participants on the mechanical horse, explaining the ease of performing this coordination (compared to the 0{degrees} and 90{degrees} target coordination). The effect of online visual feedback appeared not only on the coordination pattern itself, but most importantly on its variability during practice, including concerning initially stable coordination patterns.

neuroscience↗

bioRxiv2018

High proportion of multiple copies of Plasmodium falciparum Plasmepsin-2 gene in African isolates: Is piperaquine resistance emerging in Africa?

Emergence of Plasmodium falciparum resistance to antimalarial drugs is currently the primary rationale supporting the development of new and well-tolerated drugs. In 2014-2015, a phase 2b clinical study was conducted to evaluate the efficacy of a single oral dose of Artefenomel (OZ439)-piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria. Blood samples collected before treatment offered the opportunity to investigate the proportion of multidrug resistant parasite genotypes including P. falciparum Kelch13 mutations and copy number variation of both P. falciparum plasmepsin2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. Validated Kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated to PPQ resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (>30%).\n\nOur findings sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to decipher the genetic background associated with PPQ resistance in Africa by investigating in vitro susceptibilities to PPQ of isolates with multiple copies of the Pfpm2 gene and the urgent need to assess the risk of development of PPQ resistance, along with the efficacy of both current frontline therapies and new antimalarial combinations.

microbiology↗